Skip to main content
SpringerLink
Log in

Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The role of mesenchymal stromal cells (MSCs) in the modulation of liver transplant tolerance has attracted significant interest. However, the interaction between MSCs and Kupffer cells (KCs) has received little attention, and the effect of this interaction on liver transplant tolerance remains unclear. KCs were cultured in the presence and absence of MSCs. After 24 h, cells were treated with lipopolysaccharide (LPS), after which the production of cytokines and the expression of surface antigens were measured for cell function identification. Moreover, the effects of the KCs and the prostaglandin E2 (PGE2) levels produced by the MSCs were determined using an experimental rat liver transplantation model. Blood and liver samples were collected at three time points after transplantation for further analysis. After LPS treatment, when compared with the KC single cultures, the expression of pro-inflammatory cytokines (IL-1β, IL-6, MHC-II, CD40, CD80, and CD86) in the coculture system was down-regulated, whereas the expression of anti-inflammatory cytokines (TGF-β, IL-4, PGE2, and IL-10) was markedly increased. These data indicate that MSCs can reprogram the phenotype of KCs. However, KCs treated with miR/TNF-α (tumor necrosis factor) plasmid prior to coculture to inhibit the production of TNF-α resulted in an inhibition of the reprogramming effect of MSCs. Moreover, overexpression of PGE2 in MSCs increased the effect of MSCs on KC reprogramming. After rat liver transplantation, allograft recipients that received MSCs showed better allograft tolerance when compared with rats in which KC function was inhibited. Furthermore, rats treated with MSCs overexpressing PGE2 demonstrated the best liver tolerance of all of the groups tested. MSCs reprogram the phenotype of KCs through TNF-α and PGE2, and this process is crucial for the immunomodulatory function of MSCs in liver transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

KCs:

Kupffer cells

LPS:

Lipopolysaccharide

MSCs:

Mesenchymal stromal cells

PGE2:

Prostaglandin E2

TNF-α:

Tumor necrosis factor alpha

References

  1. Casiraghi F, Azzollini N, Todeschini M, et al. Localization of mesenchymal stromal cells dictates their immune or proinflammatory effects in kidney transplantation. Am J Transpl. 2012;12:2373–83.

    Article  CAS  Google Scholar 

  2. Niu J, Yue W, Song Y, et al. Prevention of acute liver allograft rejection by IL-10-engineered mesenchymal stem cells. Clin Exp Immunol. 2014;3:473–84.

    Article  Google Scholar 

  3. Selmani Z, Naji A, Zidi I, Favier B, et al. Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4 + CD25highFOXP3+ regulatory T cells. Stem Cells. 2008;1:212–22.

    Article  Google Scholar 

  4. Németh K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15(1):42–9.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Chen G-S, Qi H-Z. Effect of Kupffer cells on immune tolerance in liver transplantation. Asian Pac J Trop Med. 2012;5:970–2.

    Article  CAS  PubMed  Google Scholar 

  6. Van Hul N, Lanthier N, Espanol Suner R, et al. Kupffer cells influence parenchymal invasion and phenotypic orientation, but not the proliferation, of liver progenitor cells in a murine model of liver injury. Am J Pathol. 2011;179:1839–50.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Biswas SK, Chittezhath M, Shalova IN, Lim JY. Macrophage polarization and plasticity in health and disease. Immunol Res. 2012;53:11–24.

    Article  CAS  PubMed  Google Scholar 

  8. Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials. 2012;33:3792–802.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Mandal P, Pratt BT, Barnes M, McMullen MR, Nagy LE. Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J Biol Chem. 2011;286:13460–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Liaskou E, Wilson DV, Oo YH. Innate immune cells in liver inflammation. Mediat Inflamm. 2012;2012:949157.

    Google Scholar 

  11. Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–86.

    Article  CAS  PubMed  Google Scholar 

  12. Chen Y, Liu Z, Liang S, et al. Role of Kupffer cells in the induction of tolerance of orthotopic liver transplantation in rats. Liver Transpl. 2008;14(6):823–36.

    Article  PubMed  Google Scholar 

  13. Lian ZR, Xu Fl, Wang XB, Gong JP, Liu ZJ. Suppression of histone deacetylase 11 promotes expression of IL-10 in Kupffer cells and induces tolerance following orthotopic liver transplantation in rats. J Surg Res. 2011;174(2):359–68.

    Article  PubMed  Google Scholar 

  14. MacKenzie KF, Clark K, Naqvi S, et al. PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol. 2013;190:565–77.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Hegyi B, Kudlik G, Monostori E, Uher F. Activated T-cells and pro-inflammatory cytokines differentially regulate prostaglandin E2 secretion by mesenchymal stem cells. Biochem Biophys Res Commun. 2012;419(2):215–20.

    Article  CAS  PubMed  Google Scholar 

  16. van den Berk LC, Jansen BJ, Siebers-Vermeulen KG, et al. Mesenchymal stem cells respond to TNF but do not produce TNF. J Leukoc Biol. 2010;87:283–9.

    Article  PubMed  Google Scholar 

  17. Zeng WQ, Zhang JQ, Li Y, et al. A new method to isolate and culture rat kupffer cells. PLoS One. 2013;8:e70832.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Bayati V, Hashemitabar M, Gazor R, Nejatbakhsh R, Bijannejad D. Expression of surface markers and myogenic potential of rat bone marrow- and adipose-derived stem cells: a comparative study. Anat Cell Biol. 2013;46:113–21.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Zhao ZG, Xu W, Yu HP, et al. Functional characteristics of mesenchymal stem cells derived from bone marrow of patients with myelodysplastic syndromes. Cancer Lett. 2013;317:136–43.

    Article  Google Scholar 

  20. Nemeth K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Demetris AJ, Batts KP, Dhillon AP, et al. Banff schema for grading liver allograft rejection: an international consensus document. Hepatology. 1997;25:658–63.

    Article  Google Scholar 

  22. Parker GA, Picut CA. Immune functioning in non lymphoid organs: the liver. Toxicol Pathol. 2012;40:237–47.

    Article  CAS  PubMed  Google Scholar 

  23. Voswinkel J, Francois S, Simon JM, et al. Use of mesenchymal stem cells (MSC) in chronic inflammatory fistulizing and fibrotic diseases: a comprehensive review. Clin Rev Allergy Immunol. 2013;45:180–92.

    Article  PubMed  Google Scholar 

  24. Liu ZJ, Yan LN, Li SW, et al. Glycine blunts transplantative liver ischemia-reperfusion injury by down-regulation interleukin 1 receptor associated kinase-4. Acta Pharmacol Sin. 2006;27(5):1479–86.

    Article  CAS  PubMed  Google Scholar 

  25. Cho KA, Ju SY, Cho SJ, et al. Mesenchymal stem cells showed the highest potential for the regeneration of injured liver tissue compared with other subpopulations of the bone marrow. Cell Biol Int. 2009;33(7):772–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by the National Science Foundation of China (Nos. 81170442 and 81470899), the Important Scientific Research Project of the Ministry of Education (No. 211153), the National Scholarship Foundation (No. 201208505116), and the Outstanding Young Talent Fund of the Second Hospital of CQMU (2011).

Conflict of interest

The authors declare no conflicts of interest.

Author information

Author notes

    Authors and Affiliations

    1. Department of Hepatobiliary Surgery, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

      Yu You, Jianping Gong, Yue Li, Kang Yang & Zuojin Liu

    2. Department of Anesthesia, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

      Jiqin Zhang & Yupei Chen

    Authors
    1. Yu You
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Jiqin Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Jianping Gong
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yupei Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yue Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Kang Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Zuojin Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Zuojin Liu.

    Additional information

    Yu You and Jiqin Zhang contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    You, Y., Zhang, J., Gong, J. et al. Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance. Immunol Res 62, 292–305 (2015). https://doi.org/10.1007/s12026-015-8660-2

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12026-015-8660-2

    Keywords

    Search

    Navigation